Zebrafish Models for Non-Alcoholic Fatty Liver Disease Studies

Zebrafish have emerged as a versatile vertebrate model for dissecting the mechanisms of non-alcoholic fatty liver disease (NAFLD). Their hepatic anatomy and metabolic pathways closely parallel those of humans, while optical transparency and rapid development facilitate live imaging of lipid accumulation, inflammation and fibrotic progression. Genetic tractability allows both forward and reverse approaches, including transgenic overexpression, gene knockouts and chemical mutagenesis, to induce key hallmarks of NAFLD such as hepatic steatosis, oxidative stress and non-alcoholic steatohepatitis (NASH). Dietary interventions—high-fat, high-cholesterol or fructose supplementation—reproduce metabolic insults, and starvation protocols elucidate compensatory lipid transport and de novo lipogenesis. Integration of live staining, transcriptomic profiling and histological analysis provides a comprehensive view of disease initiation and progression. Rapid and cost-effective high-throughput screening in larval zebrafish accelerates the identification of candidate therapeutics targeting lipid metabolism, endoplasmic reticulum stress and inflammatory pathways. Together, these approaches have solidified zebrafish as a global platform for both mechanistic study and preclinical evaluation in NAFLD research.

Research from Nature Portfolio

Recent studies in zebrafish have highlighted the role of stress-responsive transcription factors and microenvironmental crosstalk in NAFLD. Conditional overexpression of activating transcription factor 4 (ATF4) in transgenic larvae triggered early-onset hyperlipidaemia, robust hepatic steatosis and activation of the unfolded protein response. Adult fish exhibited accumulation of lipid droplets, oxidative stress and NASH-like histopathology, while adipocyte hyperplasia underscored systemic adipogenesis. In a separate model, inducible oncogenic krasV12 expression uncovered the dynamic interplay between hepatocytes, hepatic stellate cells, neutrophils and macrophages. Serotonin released by hepatocytes and macrophages promoted stellate cell survival and activation, which in turn orchestrated pro-tumourigenic signals. These findings underscore transcriptional and cellular mechanisms driving steatosis-to-steatohepatitis transitions in zebrafish.

Zebrafish Models for Non-Alcoholic Fatty Liver Disease Studies publication trend

The graph below shows the total number of articles in zebrafish models for non-alcoholic fatty liver disease studies across all publications each year (not limited to Nature Index journals).

Technical terms

Non-alcoholic fatty liver disease (NAFLD): A spectrum of liver disorders characterised by excessive fat deposition in hepatocytes in the absence of significant alcohol consumption.

Hepatic steatosis: Accumulation of triglycerides and neutral lipids within liver cells, often the first stage of NAFLD.

Non-alcoholic steatohepatitis (NASH): An advanced form of NAFLD involving inflammation, hepatocellular injury and varying degrees of fibrosis.

Transgenic zebrafish: Zebrafish genetically engineered to express or suppress specific genes, enabling studies of disease-related pathways.

Hepatic stellate cells: Liver pericytes that, upon activation, secrete extracellular matrix proteins and contribute to fibrogenesis.

High-throughput screening: Automated assays in zebrafish larvae allowing rapid evaluation of chemical libraries for effects on lipid metabolism and liver pathology.

References

1. Comparative Study of Different Diets-Induced NAFLD Models of Zebrafish. Frontiers in Endocrinology (2018).
2. Studying non-alcoholic fatty liver disease with zebrafish: a confluence of optics, genetics, and physiology. Cellular and Molecular Life Sciences (2012).
3. The expanding role of fish models in understanding non-alcoholic fatty liver disease. Disease Models & Mechanisms (2013).
4. High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs. Nutrition & Metabolism (2015).
5. A Model Construction of Starvation Induces Hepatic Steatosis and Transcriptome Analysis in Zebrafish Larvae. Biology (2021).
6. ATF4 overexpression induces early onset of hyperlipidaemia and hepatic steatosis and enhances adipogenesis in zebrafish. Scientific Reports (2017).
7. Interaction of hepatic stellate cells with neutrophils and macrophages in the liver following oncogenic kras activation in transgenic zebrafish. Scientific Reports (2018).
8. Lipid Modulating Anti-oxidant Stress Activity of Gastrodin on Nonalcoholic Fatty Liver Disease Larval Zebrafish Model. International Journal of Molecular Sciences (2019).